Independent Prognostic Factor In Colorectal Cancer Research Articles

ISG-15 as an independent prognostic factor in Egyptian patients with colorectal carcinoma

Background and aim Colorectal cancer (CRC) is a heterogeneous disease, with a diverse immune cell infiltrate. Interferon-stimulating gene 15 (ISG-15) is a type I interferon-regulated gene that is secreted by diverse inflammatory cells. The aim of this work was to evaluate the role of ISG-15 in CRC and to correlate its expression with clinicopathological data and patient survival. Materials and methods This retrospective case–control study included 87 chemo-naive CRC cases, 12 adenomas, and 59 non-neoplastic colonic tissue cases from Egyptian patients; all cases were stained for ISG-15 antibody. Results The present study showed that high expression of ISG-15 was correlated with malignant transformation in colorectal tissues, as higher epithelial H-score of ISG-15 was significantly associated with malignant group in comparison with non-neoplastic group (P=0.004). Epithelial overexpression of ISG-15 in CRC was significantly associated with smaller tumor size (P=0.023 and 0.011). Stromal overexpression of ISG-15 in CRC was significantly associated well-differentiated tumors (P=0.026). Moreover, ISG-15 overexpression in epithelium and stroma was associated with long survival period in CRC (P=0.02 and 0.001, respectively). More importantly, ISG-15 expression, either epithelial or stromal, was an independent prognostic factor in CRC. Conclusion High expression of ISG-15 correlates with malignant transformation in colorectal tissues, as ISG-15 is overexpressed in CRC in comparison with non-neoplastic and is associated with factors of good prognosis. In CRC, ISG-15 overexpression is associated with longer overall survival. Epithelial ISG-15 expression is the most independent prognostic factor in CRC.

Expression of Raptor and Rictor and their relationships with angiogenesis in colorectal cancer.

Mammalian target of rapamycin (mTOR) has two subtypes, i.e., mTORC1 and mTORC2, which contain the Raptor and Rictor core molecules, respectively. The effect of Raptor and Rictor on hypoxia inducible factor (HIF)-1α, HIF-2α, and vascular endothelial growth factor (VEGF) in colorectal cancer (CRC) is unclear. In this work, we investigated the correlations among Raptor, Rictor, HIF-1α, HIF-2α, and VEGF expression in CRC. We subsequently analyzed the clinicopathological features of patients. Immunohistochemistry, western blot, and RT-PCR analyses were performed to detect the expression of Raptor, Rictor, HIF-1α, HIF-2α, and VEGF in 120 cases of CRC and 60 cases of normal colorectal mucosa. CD34 was used to label microvascular density (MVD), which was found to be higher in patients with positive Raptor or Rictor than in those with negative Raptor or Rictor. The positive rates of Raptor, Rictor, HIF-1α, HIF-2α, and VEGF in CRC were significantly higher than in normal colorectal mucosa. Raptor expression was positively correlated with HIF-1α and VEGF but not with HIF-2α expression. By contrast, Rictor expression was positively correlated with HIF-2α and VEGF but not with HIF-1α expression. Survival analysis further indicated that Raptor, Rictor, HIF-1α, HIF-2α, VEGF and lymph node metastasis were independent prognostic factors in CRC. To conclude, Raptor and Rictor expression was related to the initiation and development of CRC and angiogenesis in different ways. The combined detection of Raptor and Rictor is important for patients with colorectal carcinoma in prognosis and optimal therapy.

Long non-coding RNA LINC00707 acts as a competing endogenous RNA to enhance cell proliferation in colorectal cancer.

Long non-coding RNAs (lncRNAs) have been indicated to serve critical roles in cancer development and progression. Long intergenic non-protein coding RNA 70 (LINC00707) was recently reported to be an oncogene involved in the tumorigenesis of several types of human cancer. However, the clinical role, biological functions and molecular mechanism of LINC00707 in colorectal cancer (CRC) remain unclear. The aim of the present study was to investigate the biological effects and mechanism of LINC00707 in CRC. Reverse transcription-quantitative PCR was used to detect the expression levels of LINC00707 in 65 CRC tissue samples and CRC cell lines (HCT116, HT29 and SW480). Cell Counting Kit-8 and colony formation assays were performed to investigate the effects of LINC00707 on CRC cell proliferation. A dual-luciferase reporter assay was conducted to investigate the mechanisms of LINC00707 in CRC. The upregulation of LINC00707 expression was significantly associated with tumor size, stage and poor survival in patients with CRC. LINC00707 also acted as an independent prognostic factor for CRC. Functional analyses revealed that the knockdown of LINC00707 could inhibit CRC cell proliferation. Furthermore, bioinformatics analysis demonstrated that microRNA (miR)-485-5p could directly bind to LINC00707, which was confirmed by a dual-luciferase reporter assay. In conclusion, the upregulation of LINC00707 is associated with a shorter survival time in patients with CRC. Knockdown of LINC00707 may inhibit the proliferation of CRC cells by binding with miR-485-5p.

Role of extracellular LncRNA-SNHG14/miRNA-3940-5p/NAP12 mRNA in colorectal cancer

Background We aim to identify and analyze the expression of dyregulated RNAs in colorectal cancer (CRC). Methods We selected a panel of RNAs specific to CRC composed of Nucleosome Assembly Protein 1 Like 2 (NAP1L2) mRNA, LNCRNA SNHG14 small nucleolar RNA host gene 14 (LNCRNA SNHG14) and homo sapiens microRNA-3940-5p(hsa-miRNA-3940-5p) from genetic and epigenetic databases. Validation of the chosen RNAs was achieved by real time quantitative PCR in sera of patients with CRC, versus controls groups (benign lesions and healthy individual). Results We found that LLNCRNA SNHG14, hsa-miRNA-3940-5p and NAP1L2 mRNA had an excellent performance characteristics and more superior than CEA, and CA19.9 for differentiating CRC from controls. Combined expression of lncRNA SNHG14- hsa-miR-3940-5p and NAP1L2 mRNA had reached 100% sensitivity with accuracy 93%. Interestingly, serum hsa-miRNA-3940-5p could be an independent prognostic factor in CRC. Conclusion The extracellular lncRNA SNHG14- hsa-miR-3940-5p - NAP1L2 mRNA may aid in CRC management. KEY MESSAGES The extracellular RNAs provide a potential class of noninvasive biomarkers with high specificity, accuracy and stability for detection of CRC. We used insilico data analysis followed by qPCR for detection of differential NAP1L2 gene expression with the selected epigenetic regulators. Our data presented interesting biomarker panel (NAP1L2 gene, lncRNA-SNHG14 and hsa-miR-3940-5p) that may be potential for CRC diagnosis and prognosis.

Overexpression of MAGT1 is associated with aggressiveness and poor prognosis of colorectal cancer.

Tumor metastasis and anticancer drug resistance are the major causes of mortality in patients with colorectal cancer (CRC). Due to the limitations of conventional biomarkers, it is urgent to identify novel and valid biomarkers to predict the progression and prognosis of CRC. Reverse transcription-quantitative polymerase chain reaction and western blotting were used to detect MAGT1 expression in CRC clinical samples or cell lines. Bioinformatics analysis was used to investigate the association between MAGT1 alteration and clinicopathological features of patients with CRC. The present study revealed that the transcription levels of magnesium transporter 1 (MAGT1) were significantly increased in CRC tissues compared with matched adjacent normal tissues. Overexpression of MAGT1 was associated with advanced tumor stage, N and M classification. In addition, for patients who underwent chemotherapy, patients in the MAGT1-low expression group exhibited a longer overall survival (OS) time than patients in the high-expression group. Patients with CRC treated with chemotherapy had a longer OS time than those treated without chemotherapy in the MAGT1-low expression group but not in the MAGT1-high expression group. Furthermore, MAGT1 was a valid but not an independent prognostic factor for CRC. Therefore, the present study highlighted that MAGT1 may serve as a valid biomarker for predicting the development, progression and poor prognosis of CRC.

Over-expression of SOX8 predicts poor prognosis in colorectal cancer: A retrospective study.

Aberrant expression of SRY-box 8 (SOX8) is closely correlated with the development and progression of many types of cancers in human. Limited studies report the relationship between SOX8 expression and overall survival in colorectal cancer (CRC). This study aimed to collect the pathological tissues and clinical data in order to analyze the relationship between SOX8 expression and clinicopathological parameters and prognosis of CRC patients. Tissue microarrays were constructed from 424 primary CRC patients with clinicopathological information and follow-up data. Immunohistochemistry (IHC) was performed on tissue microarrays to explore the relationship between SOX8 expression and clinicopathological information and patient's prognosis. The expression of SOX8 was higher in CRC tissues than that in non-tumor adjacent tissues (NATs, P <.001). High expression of SOX8 was associated with tumor stage (P = .04) and shorter overall survival (OS) after operation of patients (P = .004). Subsequently, univariate COX analysis identified that high expression of SOX8 (P = .004), differentiation (P = .006), distant metastasis (P <.001), tumor stage (P = .003), and higher rate of lymph node metastasis (P <.001), all significantly predicted decrease in OS. Multivariate analysis demonstrated that distant metastasis (P <.001), high SOX8 expression, (P = .013) and lymph node metastasis (P <.001) were independent poor prognostic factors in CRC patients. This study showed that SOX8 is over-expressed in patients with high T stage, which affects the outcome of prognosis in CRC patients. High expression of SOX8 usually has a poor independent prognostic factor for CRC.

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma.

BackgroundSMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.MethodsWe retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.ResultsA loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancer-specific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).ConclusionsWe confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

Clinical response and prognostic significance of serum miR-497 expression in colorectal cancer.

Colorectal cancer (CRC) is a common type of cancer around the world. Detection of microRNA (miRNA) aberration in blood samples is a novel approach for CRC screening. The purpose of this study was to explore the serum miR-497 expression pattern in CRC and examine its potential usefulness as a biomarker for CRC diagnosis and prognosis. Serum miR-497 expression was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in 110 patients with CRC, 35 cases with colorectal adenoma, 54 cases with colorectal polyps, and 70 healthy individuals. The expression level of miR-497 was significantly downregulated in CRC tissues compared to the normal tissues based on the data from three independent studies GSE68204, GSE41655 and GSE35834. Compared to healthy controls, the serum miR-497 level was significantly decreased in patient with CRC or benign lesion (colorectal adenoma and polyps). Serum miR-497 level was dramatically increased in the post-operative blood samples from early stage CRC patients. Receiver-operating characteristic (ROC) analysis showed that serum miR-497 had a high sensitivity and specificity for discriminating CRC or precancerous colorectal lesion from normal controls. Moreover, low serum miR-497 expression was closely correlated with aggressive clinical features and shorter overall survival (OS). Kaplan-Meier analyses also revealed that OS was strongly associated with lymph node invasion, TNM stage and histological grade. Furthermore, univariate and multivariate analysis showed serum miR-497 was an independent prognostic factor for CRC. Collectively, serum miR-497 may serve as a promising biomarker for diagnosis and prognosis of CRC.

Long non-coding RNA IQCJ-SCHIP1 antisense RNA 1 is downregulated in colorectal cancer and inhibits cell proliferation.

IQCJ-SCHIP1 antisense RNA 1 (IQCJ-SCHIP1-AS1) was a functional novel long non-coding RNA (lncRNA) revealed by our previous expression profile. In this study, we aim to investigate its clinical relevance and biological significance in colorectal cancer (CRC). We measured the expression levels of IQCJ-SCHIP1-AS1 in 86 paired CRC tissues using quantitative RT-PCR assay, and then analyzed its association with patient prognoses. Moreover, gain-of-function and loss-of-function studies were performed to examine the biological functions of IQCJ-SCHIP1-AS1. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) were used to elucidate potential mechanisms of IQCJ-SCHIP1-AS1 in CRC. More than 2-fold decreased expression of IQCJ-SCHIP1-AS1 was found in half of CRC tissues (53.5%, 46/86). IQCJ-SCHIP1-AS1 down-regulation was correlated with poor differentiation (P=0.025), advanced depth of tumor (P=0.022), lymphatic invasion (P=0.010), advanced tumor stage (P=0.006), and poor prognosis (P=0.0027) in CRC patients. The Cox proportional hazards model demonstrated that IQCJ-SCHIP1-AS1 expression was an independent prognostic factor for CRC (HR =0.247, 95% CI: 0.081-0.752, P=0.014). Moreover, knockdown of IQCJ-SCHIP1-AS1 promoted CRC cell proliferation through increasing cell cycle progression and impairing cell apoptosis. Additionally, bioinformatics analysis showed that differential expression genes in IQCJ-SCHIP1-AS1-depleted CRC cells were enriched in the pathways of cell cycle, DNA replication, and p53. Our results demonstrate that IQCJ-SCHIP1-AS1 has an indicative tumor suppressor role and appears to be a potential prognostic factor in CRC for the first time.

High Expression of LTBP2 Contributes to Poor Prognosis in Colorectal Cancer Patients and Correlates with the Mesenchymal Colorectal Cancer Subtype.

Colorectal cancer (CRC) is a complex and heterogeneous disease with four consensus molecular subtypes (CMS1-4). LTBP2 is a member of the fibrillin/LTBP super family and plays a critical role in tumorigenesis by activating TGF-β in the CMS4 CRC subtype. So far, the expression and prognostic significance of LTBP2 in CRC remains obscure. In this study, we aimed to analyze the mRNA and protein expression levels of LTBP2 in CRC tissues and then estimate their values as a potential prognostic biomarker. We detected the mRNA expression of LTBP2 in 28 cases of fresh CRC tissues and 4 CRC cell lines and the protein expression of LTBP2 in 483 samples of CRC tissues, matched tumor-adjacent tissues, and benign colorectal diseases. LTBP2 protein expression was then correlated to patients' clinical features and overall survival. Both LTBP2 mRNA and protein expression levels in CRC tissues were remarkably superior to those in adjacent normal colorectal tissues (P = 0.0071 and P < 0.001, respectively), according to TCGA dataset of CRC. High LTBP2 protein expression was correlated with TNM stage (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), and M stage (P < 0.001). High LTBP2 protein expression was related to poor overall survival in CRC patients and was an independent prognostic factor for CRC. LTBP2 mRNA expression was especially higher in the CMS4 subtype (P < 0.001), which was confirmed in CRC cell lines. Our data suggested that LTBP2 may act as an oncogene in the development of colorectal cancer and have important significance in predicting CRC prognosis. LTBP2 could be a novel biomarker and potential therapeutic target for mesenchymal colorectal cancer and can improve the outcome of high-risk CRC.

Genetic Analysis Using a Gene Panel in 87 Caucasian Patients With Colorectal Cancer: Own Results and Review of Literature

Colorectal cancer (CRC) is the third most common cancer worldwide. The prognosis between left- and right-sided CRC differs, partly due to baseline differences as vascular supply. The purpose of the present study was to investigate whether there are genetic differences between left- and right-sided CRC. Eighty-seven patients with CRC (mean age: 61 years) were retrospectively included in the study. Blood samples were used for genetic analysis, by applying the sequencing research panel Ion AmpliSeq Colon and Lung Cancer Research Panel V2. Statistical analyses included Chi-square tests, Kaplan-Meier survival curves, and univariate/multivariate Cox-regression analyses. By testing the sequence of 22 genes included in the panel, a significant difference was detected between left- and right-sided CRC regarding the expression of BRAF and DDR2 genes, with mutations occurring more often in the right-sided CRC. In the multivariate setting, left-sided CRC only turned out as a significant positive prognostic parameter regarding progression-free survival, irrespective of the type of chemotherapy or BRAF and NRAS mutations. Tumour location was the only parameter proven to be an independent prognostic factor for CRC in the present study.

PABPC1L depletion inhibits proliferation and migration via blockage of AKT pathway in human colorectal cancer cells.

Numerous studies have demonstrated that PABPC1 participates in the process of carcinogenesis and its function is inconsistent in different types of cancers. PABPC1-like (PABPC1L) is an important paralog of PABPC1 and few studies are available on the roles of PABPC1L in colorectal cancer (CRC) development. Hence, we explored the biological function and prognostic impact of PABPC1L in CRC. The mRNA expression of PABPC1L in CRC was determined based on the data obtained from The Cancer Genome Atlas (TCGA) database. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to determine the PABPC1L mRNA expression level in CRC HT-29 and LS-174T cell lines. Kaplan-Meier method and Cox proportional-hazards model were utilized to conduct the survival and prognosis analyses. HT-29 cells with silenced PABPC1L were constructed to explore the effect of PABPC1L on cell proliferation, invasion and migration capacities using cell counting kit-8 (CCK-8), clone formation, wound-healing and Transwell assays, respectively. To uncover the potential mechanisms of how PABPC1L influences CRC proliferation and migration, we analyzed the expression of AKT, p-AKT, PI3K, and p-PI3K in HT-29 cells using western blotting. Our results revealed that PABPC1L was overexpressed in CRC tissues compared with normal tissues based on the data obtained from TCGA database. Similarly, the mRNA expression of PABPC1L was higher in HT-29 and LS-174T cells than that in CCD-18Co cells. The expression of PABPC1L in CRC was found to be significantly related to age, pathologic stage, pathologic-node, pathologic-metastasis, and death. In univariate and multivariate analyses, pathologic-tumor and pathologic-metastasis were identified as independent prognostic factors for CRC. After PABPC1L depletion, cell proliferation rate, colony numbers, and the invasive and migratory capacity of HT-29 cells were all reduced. Western blot analysis showed that reduction of PABPC1L significantly inhibited p-AKT, and p-PI3K expression level in HT-29 cells. Collectively, our results suggested that PABPC1L is a potential novel candidate oncogene in CRC, and targeting PABPC1L may provide clinical utility in CRC.

PIK3CD induces cell growth and invasion by activating AKT/GSK-3β/β-catenin signaling in colorectal cancer.

The catalytic subunit p110δ of phosphoinositide 3‐kinase (PI3K) encoded by PIK3CD has been implicated in some human solid tumors. However, its roles in colorectal cancer (CRC) remain largely unknown. Here we found that PIK3CD was overexpressed in colon cancer tissues and CRC cell lines and was an independent predictor for overall survival (OS) of patients with colon cancer. The ectopic overexpression of PIK3CD significantly promoted CRC cell growth, migration and invasion in vitro and tumor growth in vivo. In contrast, inhibition of PIK3CD by specific small‐interfering RNA or idelalisib dramatically suppressed CRC cell growth, migration and invasion in vitro and tumor growth in vivo. Moreover, PIK3CD overexpression increased AKT activity, nuclear translocation of β‐catenin and T‐cell factor/lymphoid enhancer factor (TCF/LEF) transcriptional activity and decreased glycogen synthase kinase 3β (GSK‐3β) activity, whereas PIK3CD inhibition exhibited the opposite effects. Furthermore, PIK3CD‐mediated cell growth, migration and invasion were reversed by blockade of AKT signaling or depletion of β‐catenin. In addition, PIK3CD expression in colon cancer tissues positively correlated with β‐catenin abnormal expression, which was an independent predictor for OS of colon cancer patients. Taken together, our findings demonstrate that PIK3CD is an independent prognostic factor in CRC and that PIK3CD induces CRC cell growth, migration and invasion by activating AKT/GSK‐3β/β‐catenin signaling, suggesting that PIK3CD might be a novel prognostic biomarker and a potential therapeutic target for CRC.

Expression and association of carbonic anhydrase IX and cyclooxygenase-2 in colorectal cancer

BackgroundThis work was designed to determine the relationship between hypoxia-inducible protein carbonic anhydrase IX (CA IX) and pro-inflammatory enzyme cyclooxygenase-2 (COX-2) in patients with colorectal cancer (CRC). MethodsWe examined CA IX and COX-2 expression in CRC tissues by immunohistochemical staining of 111 samples. We evaluated the correlation between the expression of these proteins and their correlation with the clinico-morphological parameters of CRC. ResultsCA IX was detected in 89 of 111 cases (80.2%). We predominantly observed membrane staining (70.3%) and a strong immunoreaction intensity (58.6%). The percentage of labeled cells in malignant lesions was less than 25% in 12.6% of cases, less than 50% in 15.3% of cases and more than 50% in 52.3% of CRC cases. The COX-2 protein was expressed in 94 of 111 cases (84.7%). We noticed only cytoplasmic localization, while immunoreaction intensity was predominantly strong (47.8%). The percentage of COX-2 positive cells was less than 25% only in 2.7% of the cases, less than 50% in 21.6% of the cases and more than 50% in 60.4% of the cases. No statistically significant correlations were observed between CA IX expression and clinico-morphological parameters. COX-2 expression was only significantly correlated with the tumor stage. Statistical analysis confirmed a significant correlation between the parameters of expression of the CA IX and COX-2 proteins. ConclusionCA IX/COX-2 interplay can promote hypoxia survival and the invasion of tumor cells. These proteins may represent independent prognostic factors of CRC.

HOXB8 enhances the proliferation and metastasis of colorectal cancer cells by promoting EMT via STAT3 activation

BackgroundPrevious studies have demonstrated that the expression of homeobox8 (HOXB8) is higher in colorectal cancer (CRC) tissues than in normal tissues; however, the precise role of HOXB8 in human CRC cells remains to be elucidated.MethodsWe generated lentiviral constructs to overexpress and silence HOXB8 in CRC cell lines, and examined their biological functions through MTT, wound healing, colony and transwell, expression of signal transducer and activator of transcription 3 (STAT3) and epithelial–mesenchymal transition (EMT) related factors through western-blot.ResultsHOXB8 knockdown inhibited cellular proliferation and invasion in vitro as well as carcinogenesis and metastasis in vivo. HOXB8 also induced EMT, which is characterized by the down-regulation of E-cadherin and the up-regulation of Vimentin, N-cadherin, Twist, Zeb1 and Zeb2. Moreover, HOXB8 activated STAT3, which is known to play an oncogenic role in diverse human malignancies.ConclusionsOur results indicate that HOXB8 may be an independent prognostic factor in CRC. Therefore, deserved a deeper research.

HCRP-1 regulates EGFR\u2013AKT\u2013BIM-mediated anoikis resistance and serves as a prognostic marker in human colon cancer

Hepatocellular carcinoma-related protein-1 (HCRP-1), a subunit of mammalian endosomal sorting complex required for transport-I (ESCRT-I), is frequently downregulated in various kinds of malignant tumors. The role of HCRP-1 in colorectal cancer (CRC) remains unknown. We investigate the clinical value of HCRP-1 and its impact on anoikis in CRC. The negative expression of HCRP-1 was significantly correlated with tumor size (P = 0.033), PT status (P = 0.001), TNM stage (P = 0.039), and histological grade (P = 0.01). Univariate and multivariate analyses revealed that HCRP-1 was an independent prognostic factor for CRC (hazard ratio (HR) = 0.237, P < 0.001 for 5-year overall survival). In the in vitro assay, we found that HCRP-1 depletion resulted in cell anoikis resistance. Knockdown of HCRP-1 suppressed Bcl-2 interacting mediator of cell death (BIM) expression, with phosphorylation of AKT and p-FoxO3a, which was reversed by AKT siRNA or AKT inhibitor. Further analysis showed that loss of HCRP-1 obviously increased the activation of EGFR. Inhibition of EGFR blocked si-HCRP1-mediated phosphorylation of EGFR, AKT, FoxO3a, and BIM expression. Moreover, the in vivo results revealed that loss of HCRP-1 promoted cancer metastasis. Our findings implied that reduced HCRP-1 expression in CRC resulted in anoikis resistance and contributed to CRC metastasis and poor prognosis. These data may help design effective therapy targeting HCRP-1 pathway to control colon cancer growth and metastasis.

The role of tissue and serum carcinoembryonic antigen in stages I to III of colorectal cancer-A retrospective cohort study.

PurposeTissue carcinoembryonic antigen (t‐CEA) and serum carcinoembryonic antigen (s‐CEA) expression profiles are the most useful tumor markers for the diagnosis and evaluation of colorectal cancer (CRC) worldwide; however, their roles in CRC progression remain controversial. This study aimed to compare the prognostic values of both s‐CEA and t‐CEA in CRC.MethodsA total of 517 patients from January 2006 to December 2010 with stages I‐III CRC were retrospectively examined, with 5‐year postoperative follow‐up and death as end‐points. T‐CEA expression, s‐CEA expression, and clinical pathological parameters were inputted into the SPSS 21.0 software. The Kaplan‐Meier method was used to analyze the 5‐year disease‐free survival (DFS) rate of patients in different tumor node metastasis (TNM) stages based on t‐CEA and s‐CEA expression.ResultsTumor differentiation and the number of positive lymph node harvests were significantly different among the t‐CEA groups (P < 0.001, P = 0.002); however, clinicopathological features showed no significant difference. The groups with high s‐CEA and t‐CEA expression had a significantly poorer prognosis than those with low s‐CEA (P = 0.021) and t‐CEA (P < 0.01) expression, respectively. The multivariate analysis demonstrated that t‐CEA was an independent prognostic factor in CRC (P < 0.001), but s‐CEA was not (P = 0.339). The 5‐year disease‐free survival rates among the t‐CEA groups were significantly different in stages I, II, and III of CRC (P = 0.001, P < 0.001, P < 0.001), whereas in the s‐CEA groups, this difference was observed only in stage III (P = 0.014).ConclusionThis study shows that postoperative t‐CEA expression is an independent factor associated with poorer CRC prognosis and has a higher prognostic value than that of preoperative s‐CEA expression.

Upregulation of AKIP1 contributes to metastasis and progression and predicts poor prognosis of patients with colorectal cancer.

BackgroundA kinase-interacting protein 1 (AKIP1) has been reported to play an important role in the development and progression of cancer. However, the clinicopathological and biological roles of AKIP1 in colorectal cancer (CRC) remain largely unknown. The aim of this study was to investigate AKIP1 protein expression in CRC and determine the correlation between AKIP1 protein expression and clinicopathological features, as well as prognosis in CRC patients.Materials and methodsAKIP1 protein expression was determined by immunohistochemical analysis using tissue microarrays of CRC. We also used an siRNA approach to knock down AKIP1 expression and determine the effect of AKIP1 on CRC cell migration by transwell analysis.ResultsAKIP1 expression in CRC tissue was significantly higher compared with that of noncancerous colorectal mucosa (P<0.001). Further analysis showed that AKIP1 expression was significantly associated with tumor diameter, TNM stage, and lymph node metastasis (P<0.05). Kaplan–Meier survival analysis demonstrated that patients with a positive AKIP1 expression had significantly poorer overall survival rates when compared with those with negative AKIP1 expression (P=0.031). Multivariate analysis using the Cox proportional hazard model, however, revealed that AKIP1 expression was not a significant independent prognostic factor for CRC. Transwell assay showed that the migration potential of si-AKIP1-transfected cells was significantly reduced when compared with control cells.ConclusionElevated AKIP1 expression may contribute to metastasis and progression of CRC. Moreover, high AKIP1 expression in CRC significantly correlated with a patient’s shorter survival time. Therefore, AKIP1 may be a useful prognostic marker for CRC and a promising novel target for the treatment of CRC.

Relationships of kin17 protein expression with clinical features and prognosis of colorectal cancer

Background: To investigate the relationships of kin17 protein expression with the clinical features and prognosis of colorectal cancer (CRC). Methods: The clinicopathological data and paraffin specimens of 135 CRC patients in the First Affiliated Hospital of Nanchang University from November 2008 to November 2009 were collected. Immunohistochemistry was used to detect the kin17 protein expression in paraffin-embedded specimens, and the relationship between the kin17 protein expression and the clinicopathological features and prognosis of CRC were analyzed. Results: The kin17 protein expression was significantly higher in cancer tissue than in paracancerous tissue (49.6% vs . 14.8%, P vs . 60.6%, P vs . 100%, P vs . 52.9%, P Conclusions: The kin17 protein expression is remarkably up-regulated in CRC tissue, and its expression level is related to the depth of tumor invasion, lymph node metastasis/distant metastasis, clinical stage, histological grade, and vascular invasion. Also, kin17 protein is an independent prognostic factor for CRC.

Abstract 5226: Tiam1 is a key modulator of chemoresistance in colorectal cancer

Abstract Purpose: Emerging evidence indicates that a small subpopulation of cancer cells with stem cell-like properties are responsible for acquisition of drug resistance in colorectal cancer (CRC). Intriguingly, the acquisition of such a stem-like state and subsequent drug resistance has been shown to be induced by the tumor microenvironment. In particular, cancer associated fibroblasts (CAFs) have been identified as a key component of tumor microenvironment which promote cancer stemness. Wnt signaling is a well-recognized pathway that drives self-renewal, and recently one of the Wnt-responsive genes, Tiam1, a guanine nucleotide exchange factor specific for Rac1, was shown to be overexpressed in CRC and associated with an aggressive cancer phenotype. Herein, we have investigated Tiam1 as a key modulator of chemoresistance in CRC. Methods: Tiam1 expression was assessed in resected CRC tissues from 300 patients who did or did not respond to chemotherapy. We used siRNA and CRISPR/CAS9 approach in three cell lines and animal models to examine whether inhibition of Tiam1 affects chemosensitivity in CRC. In addition, we established CRC patient derived-CAFs and examined whether the drug sensitivity of CRC cells was altered by supplementation of CAF-derived conditioned medium. Results: High Tiam1 expression significantly correlated with poor prognosis in CRC patients (P=0.032), and emerged as an independent prognostic factor (HR 5.06, 95% CI 1.10-23.2, P=0.038). In addition, Tiam1 overexpression is associated with patients who did not respond to chemotherapy (P=0.0005). We demonstrated that siRNA-mediated inhibition of Tiam1 enhanced sensitivity to three chemotherapeutic drugs (5-fluorouracil, oxaliplatin and irinotecan), and reduced tumor invasiveness in HCT116, SW480 and SW620 cell lines. Silencing of Tiam1 resulted in downregulation of stemness-related genes and spheroid formation ability. Furthermore, we validated that Tiam1-knockdown enhanced drug sensitivity and decreased the expression of stemness-related genes in xenograft tumors. Finally, we illustrated that the conditioned medium (CM) derived from CAFs led to increased stemness and chemoresistance in CRC cells through Tiam1 overexpression, and silencing of Tiam1 in CAFs resulted in reversal of stemness and chemoresistance properties. From a mechanistic standpoint, the target genes of Wnt signaling were also upregulated during co-culture with CM in CRC cells. Conclusion: We have firstly demonstrated that Tiam1 is overexpressed in CRC patients who did not respond to chemotherapeutic drugs; and furthermore, high Tiam1 expression emerged as an independent prognostic factor in CRC. Mechanistically, CAFs enhanced CRC chemoresistance through Tiam1 overexpression. Collectively, these results suggest that Tiam1 suppression in stroma may sensitize CRC cells to chemotherapeutic agents, suggesting that Tiam1 may be an attractive therapeutic target in colorectal cancer. Citation Format: Daisuke Izumi. Tiam1 is a key modulator of chemoresistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5226.